2-Amino-3,4-dihydropyridines used to effect coronary vessel dilation and treat hypertension

ABSTRACT

3-Substituted 2-amino-3,4-dihydropyridine-3-carboxylic acid esters are produced by reacting 2-amino-1,4-dihydropyridine-3-carboxylic acid esters with an alkylating agent in the presence of an inert organic solvent at a temperature of from 20° C to 200° C. The compounds, of which 2-amino-3,6-dimethyl-4-phenyl-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester is a typical embodiment, possess antihypertensive and coronary dilating properties.

This is a division of copending application Ser. No. 445,166, filed Feb.25, 1974.

The present invention relates to 2-amino-3,4-dihydropyridines, to anovel process for their production, to pharmaceutical compositionsuseful for their antihypertensive effect and coronary dilating effectusing said compounds as the active agent, and to methods of treatinghypertension in humans and animals and methods of effecting coronarydilation in humans and animals using said compounds.

It is known in the art that the reaction of glutaronitriles withhydrogen halides and subsequent elimination of hydrogen halide produces2-amino-3,4-dihydropyridines: ##STR1## wherein X is chloro, bromo oriodo; and

R is hydrogen, or phenyl (compare L. G. Duquette and F. Johnson,Tetrahedron 23, 4517 (1967)).

However, to date nothing has been disclosed concerning3,4-dihydropyridines which are amino-substituted in the 2- or the 2- and6-positions and have carbonylic groups in the 3- and 5-positions.

More specifically the present invention is concerned with2-amino-3,4-dihydropyridines of the formula: ##STR2## wherein R¹ ishydrogen, straight or branched chain lower alkyl, or amino;

R² is straight or branched chain lower alkyl or OR' wherein R' is astraight or branched chain saturated, partially unsaturated, orunsaturated lower hydrocarbon, or said hydrocarbon interrupted by 1 or 2oxygen atoms;

R³ is a straight chain, branched chain, or cyclic unsaturated, partiallyunsaturated, or unsaturated hydrocarbon of up to 6 carbon atoms; aryl of6 to 10 carbon atoms unsubstituted or substituted by 1, 2 or 3 of thesame or different substituents selected from the group consisting ofalkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen,azido, cyano, phenyl, nitro, trifluoromethyl, carbalkoxy of 1 to 4carbon atoms in the alkoxy moiety and SO_(n) -alkyl of 1 to 4 carbonatoms in the alkyl moiety wherein n is 0, 1 or 2; quinolyl; isoquinolyl;pyridyl; pyrimidyl; thenyl; furyl; or pyrryl;

R⁴ is a straight or branched chain saturated, partially unsaturated, orunsaturated hydrocarbon of 1 to 6 carbon atoms; and

R⁵ is a straight or branched chain saturated, partially unsaturated, orunsaturated hydrocarbon of 1 to 6 carbon atoms, or benzyl.

The 2-amino-3,4-dihydropyridines of the present invention are producedby reacting a 2-amino-1,4-dihydropyridine of the formula: ##STR3##wherein R¹, R², R³ and R⁴ are as above defined, with an alkylating agentof the formula:

    R.sup.5 X                                                  (III)

wherein

R⁵ is as above defined, and

X is a moiety capable of being cleaved during the alkylation reaction,in the presence of an inert organic solvent at a temperature of from 20°C to 200° C.

The compounds of the present invention are useful for theirantihypertensive and coronary dilating effects. These compounds havebeen found to exhibit strong and long-lasting antihypertensive effectsand strong and long-lasting coronary dilating effects.

It is surprising that the compounds of the present invention areproduced in such good yields and in such high purity by the reaction setforth above since according to the prior art, the formation ofN-alkylation products of the formula IV or V, below, would have beenexpected: ##STR4## (compare A. E. Tschitschibabin, R. A. Konowalowa andA. A. Konowalowa, Ber. 54, 841 (1921)).

However, the process of the present invention described above yieldsonly the C-alkylation products of formula I, with relocation of thedouble bond from the 2,3-position of the starting material to the1,2-position of the final product.

The process of the present invention is particularly advantageousbecause it makes possible both high yields of the compounds of thepresent invention and yields of such compounds in a high degree ofpurity. In addition, the process is carried out as a one-stage process,thus requiring little technical effort. It is also highly economical.

The course of the process of the present invention, when2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine3,5-dicarboxylicacid diethyl ester and methyl iodide are reacted in the presence of analkali metal alcoholate, is illustrated by the following equation:##STR5## wherein R is lower alkyl, especially ethyl.

According to one embodiment of the present invention:

R¹ is hydrogen, straight or branched chain lower alkyl, or amino;

R² is straight or branched chain lower alkyl or OR' wherein R' isstraight or branched chain lower alkyl, lower alkenyl, lower alkinyl orlower alkyl, lower alkenyl or lower alkinyl interrupted by 1 or 2 carbonatoms;

R³ is straight or branched chain alkyl of 1 to 6 carbon atoms; straightor branched chain alkenyl of 2 to 6 carbon atoms; straight or branchedchain alkinyl of 2 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms;cycloalkenyl of 3 to 6 carbon atoms; aryl of 6 to 10 carbon atomsunsubstituted or substituted by 1, 2 or 3 of the same or differentsubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, azido, cyano,phenyl, nitro, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in thealkoxy moiety and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkylmoiety wherein n is 0, 1 or 2; quinolyl; isoquinolyl; pyridyl;pyrimidyl; thenyl; furyl; or pyrryl;

R⁴ is straight or branched chain alkyl of 1 to 6 carbon atoms, straightor branched chain alkenyl of 2 to 6 carbon atoms, or straight orbranched chain alkinyl of 2 to 6 carbon atoms; and

R⁵ is straight or branched chain alkyl of 1 to 6 carbon atoms, straightor branched chain alkenyl of 2 to 6 carbon atoms, straight or branchedchain alkinyl of 2 to 6 carbon atoms, or benzyl.

According to another embodiment of the present invention:

R¹ is straight or branched chain alkyl of 1 to 4 carbon atoms, or amino;

R² is straight or branched chain alkyl of 1 to 4 carbon atoms, or OR'wherein R' is straight or branched chain alkyl of 1 to 4 carbon atoms,straight or branched chain alkenyl of 2 to 4 carbon atoms, straight orbranched chain alkinyl of 2 to 4 carbon atoms, straight or branchedchain alkyl of 1 to 4 carbon atoms interrupted by one oxygen atom orstraight or branched chain alkenyl of 2 to 4 carbon atoms interrupted byone oxygen atom;

R³ is straight or branched chain alkyl of 1 to 6 carbon atoms; straightor branched chain alkenyl of 2 to 6 carbon atoms; straight or branchedchain alkinyl of 2 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms;phenyl unsubstituted or substituted by 1 or 2 of the same or differentsubstituents selected from the group consisting of alkyl of 1 to 4carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, azido, cyano,nitro, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxymoiety and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkyl moietywherein n is 0, 1 or 2; naphthyl; quinolyl; isoquinolyl; pyridyl;pyrimidyl; thenyl; or furyl;

R⁴ is straight or branched chain alkyl of 1 to 4 carbon atoms, straightor branched chain alkenyl of 2 to 4 carbon atoms or straight or branchedchain alkinyl of 2 to 4 carbon atoms; and

R⁵ is straight or branched chain alkyl of 1 to 4 carbon atoms, straightor branched chain alkenyl of 2 to 4 carbon atoms, straight or branchedchain alkinyl of 2 to 4 carbon atoms, or benzyl.

According to another embodiment of the present invention:

R¹ is straight or branched chain alkyl of 1 to 4 carbon atoms, or amino;

R² is straight or branched chain alkyl of 1 to 4 carbon atoms, or OR'wherein R' is straight or branched chain alkyl of 1 to 4 carbon atoms,straight or branched chain alkenyl of 2 to 4 carbon atoms, straight orbranched chain alkyl of 1 to 4 carbon atoms interrupted by one oxygenatom, or straight or branched chain alkenyl of 2 to 4 carbon atomsinterrupted by one oxygen atom;

R³ is straight or branched chain alkyl of 1 to 6 carbon atoms, or phenylunsubstituted or substituted by alkyl of 1 or 2 carbon atoms, alkoxy of1 or 2 carbon atoms, fluorine, chlorine, bromine, cyano, nitro,trifluoromethyl, or thioalkyl of 1 to 4 carbon atoms;

R⁴ is straight or branched chain alkyl of 1 to 4 carbon atoms; and

R⁵ is straight or branched chain alkyl of 1 to 4 carbon atoms, orbenzyl.

According to another embodiment of the present invention:

R¹ is alkyl of 1 or 2 carbon atoms, or amino;

R² is alkoxy of 1 to 4 carbon atoms;

R³ is alkyl of 1 or 2 carbon atoms, or phenyl unsubstituted orsubstituted by alkyl of 1 or 2 carbon atoms, chlorine, bromine, cyano,nitro, or thioalkyl of 1 or 2 carbon atoms;

R⁴ is straight or branched chain alkyl of 1 to 4 carbon atoms; and

R⁵ is straight or branched chain alkyl of 1 to 4 carbon atoms, orbenzyl.

According to another embodiment of the present invention:

R¹ is methyl, or amino;

R² is ethoxy, or propoxy;

R³ is methyl, phenyl, nitrophenyl, thiomethylphenyl, or cyanophenyl;

R⁴ is ethyl, or isopropyl; and

R⁵ is methyl, ethyl, or benzyl.

The 2-amino-1,4-dihydropyridines of the formula II used as startingsubstances in the process of the present invention are not per se knownbut can be prepared by one of the following methods:

a. Reaction of an α,β-unsaturated dicarbonyl compound with anamidinoacetic acid ester: ##STR6##

b. Reaction of an aldehyde with a twice-molar amount of an amidinoaceticacid ester: ##STR7##

c. Reaction of an α-β-unsaturated β-ketonitrile with an amidinoaceticacid ester: ##STR8##

The amidinoacetic acid esters (S. M. McElvain and B. E. Tate, J.A.C.S.73, 2760 (1951)) and the α,β-unsaturated compounds (org. Reactions XV,204 et seq.) can be prepared by known methods.

Representative 2-amino- (or 2,6-diamino)-1,4-dihydropyridines (II)include:

2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester,

2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester,

2,6-diamino-4-(α-pyridyl)-3,5-dicarboxylic acid diisopropyl ester,

2-amino-6-ethyl-4-(2'-cyanophenyl)-1,4-dihydropyridine3,5-dicarboxylicacid diethyl ester,

2-amino-6-methyl-5-acetyl-4-(3'-nitrophenyl)-3-carboxylic acid ethylester,

2-amino-6-methyl-4-(3'-nitrophenyl)-3,5-dicarboxylic acid 3-ethylester-5-propargyl ester,

2-amino-6-methyl-4-(3'-trifluoromethylphenyl)-1,4-dihydropyridine-3-ethylester-5-β-methoxyethylester,

2-amino-6-methyl-4-(biphenyl-2')-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester,

2-amino-6-methyl-4-(2'-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester-5-ethyl ester,

2-amino-6-ethyl-4-(2'-fluorophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester-5-isopropyl ester,

2,6-diamino-4-(3'-azidophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester,

2-amino-6-isopropyl-4-(naphthyl-1')-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester-5-allyl ester,

2,6-diamino-4-(4'-mercaptomethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester,

2,6-diamino-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid 3-ethylester-5-isopropyl ester,

2-amino-6-methyl-4-(3'-carboxymethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester,

2-amino-6-methyl-4-(quinolyl-4')-1,4-dihydropyridine-3,5-dicarboxylicacid diisopropyl ester,

2,6-diamino-4-(isoquinolyl-1')-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester,

2-amino-6-methyl-4-(3'-nitro-6'-chlorophenyl)-1,4-dihydropyridine-3-ethylester-5-methyl ester,

2-amino-6-methyl-4-(3',4',5'-trimethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester,

2,6-diamino-4-(pyrimidyl-2')-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester,

2-amino-6-methyl-4-(furyl-2')-1,4-dihydropyridine-3,5-dicarboxylic acid3-methyl ester-5-ethyl ester,

2-amino-6-methyl-4-(thenyl-2')-1,4-dihydropyridine-3,5-dicarboxylic acid3-ethyl ester-5-isopropyl ester, and

2-amino-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid3-allyl ester.

X is preferably chlorine, bromine, iodine, a sulphuric acid ester of theformula -O-SO₂ OR⁵ wherein R⁵ is as above defined, a sulphonic acid ofthe formula -OSO₂ R⁶ wherein R⁶ is aryl of 6 to 10 carbon atomsespecially mono-aryl, or lower alkyl, a phosphonic acid ester of theformula -OPO(OR⁵)₂ wherein R⁵ is as above defined or dialkyloxonium ofthe formula ##STR9## wherein Y.sup.θ is BF₄ .sup.θ, and R⁵ is alkyl of 1to 6 carbon atoms.

The alkylating agents of the formula III are either known per se or canbe prepared according to techniques per se known.

Representative alkylating agents (III) which are used in the process ofthe present invention include:

methyl chloride, bromide and iodide,

ethyl chloride, bromide and iodide,

isopropyl bromide,

n-propyl iodide,

n-butyl bromide,

2-iodopentane

benzyl chloride, bromide and iodide,

methyl, ethyl and n-propyl tosylates,

dimethyl, diethyl, dipropyl and dibutyl sulphates,

triethyl phosphate, and

triethyloxonium fluoborate.

The process of the present invention is preferably carried out in thepresence of a basic reagent. Preferred basic reagents include alkalimetal alcoholates in stoichiometric proportions, amines, alkali metalcorbonates and alkaline earth metal carbonates.

Any inert organic solvent can be used as a suitable diluent. Preferredsolvents include alcohols such as methanol, ethanol and propanol, etherssuch as dioxane and diethyl ether, pyridine, dimethylformamide,dimethylsulphoxide and acetonitrile.

The reaction temperatures can be varied within a substantial range asindicated above. The preferred temperature range is between 50° C and150° C and especially at the boiling point of the solvent.

The process of the present invention may be carried out underatmospheric pressure or under elevated pressure. It is preferred thatatmospheric pressure be used.

In carrying out the process of the present invention, the reactants areusually employed in molar amounts but a slight excess of alkylatingagent is not objectionable.

The compounds of the present invention have demonstrated the followingactivity in test animals:

1. On parenteral, oral and perlingual administration the new compoundsproduce a distinct and long-lasting dilation of the coronary vessels.This action on the coronary vessels is intensified by a simultaneousnitrite-like effect of reducing the load on the heart. They influence ormodify the heart metabolism in the sense of an energy saving.

2. The new compounds lower the blood pressure of normotonic andhypertonic animals and can thus be used as antihypertensive agents.

3. The excitability of the stimulus formation and excitation conductionsystem within the heart is lowered, so that an anti-fibrillation actiondemonstrable at therapeutic doses results.

4. The tone of the smooth muscle of the vessels is greatly reduced underthe action of the compounds. This vascular-spasmolytic action can takeplace throughout the entire vascular system or can manifest itself moreor less isolated in circumscribed vascular regions (for example, thecentral nervous system).

5. The new compounds have strong muscular-spasmolytic actions whichmanifest themselves on the smooth muscle of the stomach, the intestinaltract, the urogenital tract and the respiratory system.

6. The new compounds influence the cholesterol level and lipid level ofthe blood.

The coronary action of the compounds of the present invention preparedin the following examples is shown by way of illustration in Table I:

                  Table I                                                         ______________________________________                                        Compound of                                                                              Distinctly discernible rise in oxygen                              Example No.                                                                              saturation in the coronary sinus                                   ______________________________________                                                     Dose      Duration of action                                     1          2.0 mg/kg body wt.                                                                            20       minutes                                    1a        0.1 mg/kg body wt.                                                                            45       minutes                                    1b        2.0 mg/kg body wt.                                                                            3        minutes                                    1d        0.5 mg/kg body wt.                                                                            60       minutes                                    1f        0.5 mg/kg body wt.                                                                            >120     minutes                                   2          5.0 mg/kg. body wt.                                                                           45       minutes                                   3          3.0 mg/kg body wt.                                                                            20       minutes                                   4          2.0 mg/kg body wt.                                                                            20       minutes                                   ______________________________________                                    

The coronary action was determined on narcotised, heart-catheterisedmongrel dogs by measuring the rise in oxygen saturation in the coronarysinus after intravenous administration of the compounds.

The action of some compounds according to the invention on the bloodpressure can be seen from Table II. The dose quoted in the second columnrelates to a blood pressure lowering of at least 15 mm Hg.

                  Table II                                                        ______________________________________                                                                   Blood pressure                                                                lowering in                                                    Toxicity in mice:                                                                            hypertonic rats:                                   Compound of mg/kg administer-                                                                            mg/kg adminis-                                     Example No. ed orally      tered orally                                       ______________________________________                                        1           >3,000          from 31.5                                          1f         --              from  1.0                                         4            3,000          from 31.5                                         ______________________________________                                    

The pharmaceutical compositions of the present invention contain a majoror minor amount e.g. 0.1 to 99.5%, preferably 0.5 to 90% of at least one2-amino-3,4-dihydropyridine as above defined in combination with apharmaceutically acceptable nontoxic, inert diluent or carrier, thecarrier comprising one or more solid, semi-solid or liquid diluent,filler and formulation adjuvant which is nontoxic, inert andpharmaceutically acceptable. Such pharmaceutical compositions arepreferably in dosage unit form; i.e., physically discrete unitscontaining a predetermined amount of the drug corresponding to afraction or multiple of the dose which is calculated to produce thedesired therapeutic response. The dosage units can contain one, two,three, four or more single doses or, alternatively, one-half, third orfourth of a single dose. A single dose preferably contains an amountsufficient to produce the desired therapeutic effect upon administrationat one application of one or more dosage units according to apredetermined dosage regimen, usually a whole, half, third or quarter ofthe daily dosage administered once, twice, three or four times a day.Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefullyadjusted, utilizing sound professional judgment and considering the age,weight and condition of the recipient, the route of administration andthe nature and gravity of the illness, generally the dosage administeredintravenously will be from 0.01 to 10 mg/kg, preferably 0.1 to 5 mg/kg,of body weight per day, and the dosage administered orally will be from0.1 to 50 mg/kg, preferably 1 to 20 mg/kg, of body weight per day. Insome instances a sufficient therapeutic effect can be obtained at alower dose while in others, a larger dose will be required.

Oral administration can be effected utilizing solid and liquid dosageunit forms such as powders, tablets, dragees, capsules, granulates,suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine sizeand mixing with a similarly comminuted pharmaceutical carrier such as anedible carbohydrate as for example starch, lactose, sucrose, glucose ormannitol. Sweetening, flavoring, preservative, dispersing and coloringagents can also be present.

Capsules are made by preparing a powder mixture as described above andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture,granulating or slugging, adding a lubricant and disintegrant andpressing into tablets. A powder mixture is prepared by mixing thecompound, suitably comminuted, with a diluent or base as describedabove, and optionally with a binder such as carboxymethyl, cellulose, analginate, gelatin, or polyvinyl pyrrolidone, a solution retardant suchas paraffin, a resorption accelerator such as a quaternary salt and/oran absorption agent such as bentonite, kaolin or dicalcium phosphate.The powder mixture can be granulated by wetting with a binder such assyrup, starch paste, acacia mucilage or solutions of cellulosic orpolymeric materials and forcing through a screen. As an alternative togranulating, the powder mixture can be run through the tablet machineand the resulting imperfectly formed slugs broken into granules. Thegranules can be lubricated to prevent sticking to the tablet formingdies by means of the addition of stearic acid, a stearate salt, talc ormineral oil. The lubricated mixture is then compressed into tablets. Themedicaments can also be combined with free flowing inert carriers andcompressed into tablets directly without going through the granulatingor slugging steps. A clear or opaque protective coating consisting of asealing coat of shellac, a coating of sugar or polymeric material and apolish coating of wax can be provided. Dyestuffs can be added to thesecoatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavored aqueous sucrose solution while elixirsare prepared through the use of a nontoxic alcoholic vehicle.Suspensions can be formulated by dispersing the compound in a nontoxicvehicle. Solubilizers and emulsifiers such as ethoxylated isostearylalcohols and polyoxyethylene sorbitol esters, preservatives, flavoradditives such as peppermint oil or saccharin, and the like can also beadded.

Where appropriate, dosage unit formulations for oral administration canbe microencapsulated. The formulation can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

Parenteral administration can be effected utilizing liquid dosage unitforms such as sterile solutions and suspensions intended forsubcutaneous, intramuscular or intravenous injection. These are preparedby suspending or dissolving a measured amount of the compound in anontoxic liquid vehicle suitable for injection such as an aqueous oroleaginous medium and sterilizing the suspension or solution.Alternatively, a measured amount of the compound is placed in a vial andthe vial and its contents are sterilized and sealed. An accompanyingvial or vehicle can be provided for mixing prior to administration.Nontoxic salts and salt solutions can be added to render the injectionisotonic. Stabilizers, preservatives and emulsifiers can also be added.

Rectal administration can be effected utilizing suppositories in whichthe compound is admixed with low melting water soluble or insolublesolids such as polyethylene glycol, cocoa butter, higher esters as forexample myristyl palmitate, or mixtures thereof.

Topical administration can be effected utilizing solid dosage unit formssuch as powders or liquid or semi-liquid dosage unit forms such assolutions, suspensions, ointments, pastes, creams and gels. The powdersare formulated utilizing such carriers as talc, bentonite, silicic acid,polyamide powder and the like. Liquid and semiliquid formulations canutilize such carriers, in addition to those described above, aspolyethylene glycol, vegetable and mineral oils, alcohols such asisopropanol and the like. Other excipients such as emulsifiers,preservatives, colorants, perfumes and the like can also be present.Formulations can also be administered as an aerosol, utilizing the usualpropellants such as the chlorofluorohydrocarbons.

The preferred daily dose for intravenous administration is 0.5 mg to 1.0g, especially 5 mg to 500 mg, of active ingredient; the preferred dailydose for oral administration is 5 mg to 5.0 g, especially 50 mg to 2.0g, of active ingredient. The preferred administration is oral orintravenous.

The following non-limitative examples more particularly illustrate thepresent invention:

EXAMPLE 1 ##STR10##

A solution of 33.0 g of2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol isbrought to the boil and treated with 15 g of methyl iodide. Afterboiling for a further 60 minutes under reflux, the mixture isconcentrated by distillation and the residue is taken up in 300 ml ofchloroform and extracted by shaking twice with 100 ml of water.Concentration of the organic phase and recrystallization from ethanolgives 18.6 g (54% of theory) of2-amino-3,6-dimethyl-4-phenyl-3,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 139° C.

EXAMPLE 1a ##STR11##

In a manner analogous to that set forth in Example 1 above, 37.4 g of2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester, 6.8 g of sodium ethylate and 15 g of methyl iodidein 500 ml of ethanol gave2-amino-3,6-dimethyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 115° C (19.8 g, 51% of theory).

EXAMPLE 1b ##STR12##

In a manner analogous to that set forth in Example 1 above, 26.7 g of2-amino-4,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethylester, 6.8 g of sodium ethylate and 15 g of methyl iodide in 300 ml ofethanol gave2-amino-3,4,6-trimethyl-3,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester of melting point 121° C (17.7 g, 62% of theory).

EXAMPLE 1c ##STR13##

In a manner analogous to that set forth in Example 1 above, 37.5 g of2-amino-6-methyl-4-(4'-methylmercaptophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester, 6.8 g of sodium ethylate and 15 g of methyl iodidein 600 ml of ethanol gave2-amino-3,6-dimethyl-4-(4'-methylmercaptophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 158° C (22.2 g, 57% of theory).

EXAMPLE 1d ##STR14##

In a manner analogous to that set forth in Example 1 above, 11.7 g of2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester-5-ethyl ester, 2.1 g of sodium ethylate and 5 gof methyl iodide in 150 ml of ethanol gave2-amino-3,6-dimethyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid 3-isopropyl ester-5-ethyl ester of melting point 114° C (4.7 g, 39%of theory).

EXAMPLE 1e ##STR15##

In a manner analogous to that set forth in Example 1 above, 6.8 g of2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester-5-β-methoxyethyl ester, 1.2 g of sodium ethylate and2.5 g of methyl iodide in 80 ml of ethanol gave2-amino-3,6-dimethyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid 3-ethyl ester-5-β-methoxyethyl ester of melting point 117° C (4.1g, 56% of theory).

EXAMPLE 1f ##STR16##

In a manner analogous to that set forth in Example 1 above, 36.5 g of2-amino-6-methyl-4-(2'-cyanophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester, 6.8 g of sodium ethylate and 15 g of methyl iodidein 600 ml of ethanol gave2-amino-3,6-dimethyl-4-(2'-cyanophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 169° C (26 g, 68% of theory).

EXAMPLE 2 ##STR17##

A solution of 37.4 g of2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol isbrought to the boil and treated with 10.9 g of ethyl bromide. Afterboiling for a further 60 minutes under reflux, the mixture isconcentrated by distillation and the residue is taken up in 300 ml ofchloroform and extracted by shaking twice with 100 ml of water.Concentration of the organic phase and recrystallization from ethanolgave 2-amino-3-ethyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point122°-3° C (16.5 g, 41% of theory).

EXAMPLE 3 ##STR18##

A solution of 37.4 g of2-amino-6-methyl-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol isbrought to the boil and treated with 17.1 g of benzyl bromide. Afterboiling for a further 60 minutes under reflux, the mixture isconcentrated by distillation and the residue is taken up in 300 ml ofchloroform and extracted by shaking twice with 100 ml of water.Concentration of the organic phase and recrystallization from ethanolgave2-amino-3-benzyl-6-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 208° C (29.4 g, 63% of theory).

EXAMPLE 4 ##STR19##

A solution of 37.5 g of2,6-diamino-4-(3'-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic aciddiethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol wastreated with 15 g of methyl iodide at the boil. After a further 60minutes under reflux, the mixture was concentrated by distillation. Theresidue is taken up in 300 ml of chloroform and extracted by shakingtwice with 100 ml of water, and the organic phase is concentrated.Recrystallization of the residue from ethanol gave2.6-diamino-3-methyl-4-(3'-nitrophenyl)-3,4-dihydropyridine-3,5-dicarboxylicacid diethyl ester of melting point 142° C (18 g, 41.5% of theory).

What is claimed is:
 1. A pharmaceutical composition useful for effectingcoronary vessel dilation in humans and other animals and for treatinghypertension in humans and other animals which comprises a coronaryvessel dilating amount or an antihypertensive amount of a compound ofthe formula: ##STR20## wherein R¹ is hydrogen, straight or branchedchain lower alkyl, or amino;R² is straight or branched chain lower alkylor OR' wherein R' is straight or branched chain lower alkyl, loweralkenyl, lower alkynyl or alkoxyalkyl of 2 to 4 carbon atoms; R³ isstraight or branched chain alkyl of 1 to 6 carbon atoms; straight orbranched chain alkenyl of 2 to 6 carbon atoms; straight or branchedchain alkynyl of 2 to 6 carbon atoms; or unsubstituted or substitutedphenyl or naphthyl which when substituted bears 1, 2 or 3 of the same ordifferent substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, azido, cyano,phenyl, nitro, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in thealkoxy moiety and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkylmoiety wherein n is 0, 1 or 2; R⁴ is straight or branched chain alkyl of1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbonatoms, or straight or branched chain alkynyl of 2 to 6 carbon atoms; andR⁵ is straight or branched chain alkyl of 1 to 6 carbon atoms, straightor branched chain alkenyl of 2 to 6carbon atoms, straight or branchedchain alkynyl of 2 to 6 carbon atoms, or benzyl,in combination with apharmaceutical acceptable nontoxic inert carrier.
 2. A compositionaccording to claim 1 whereinR¹ is straight or branched chain alkyl of 1to 4 carbon atoms, or amino; R² is straight or branched chain alkyl of 1to 4 carbon atoms, or OR' wherein R' is straight or branched chain alkylof 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4carbon atoms, straight or branched chain alkynyl of 2 to 4 carbon atoms,or alkoxyalkyl of 2 to 4 carbon atoms; R³ is straight or branched chainalkyl of 1 to 6 carbon atoms; straight or branched chain alkenyl of 2 to6 carbon atoms; straight or branched chain alkynyl of 2 to 6 carbonatoms; phenyl unsubstituted or substituted by 1 or 2 of the same ordifferent substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, azido, cyano,nitro, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxymoiety and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkyl moietywherein n is 0, 1 or 2; or naphthyl; R⁴ is straight or branched chainalkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to4 carbon atoms or straight or branched chain alkynyl of 2 to 4 carbonatoms; and R⁵ is straight or branched chain alkyl of 1 to 4 carbonatoms, straight or branched chain alkenyl of 2 to 4 carbon atoms,straight or branched chain alkynyl of 2 to 4 carbon atoms, or benzyl. 3.A composition according to claim 1 whereinR¹ is straight or branchedchain alkyl of 1 to 4 carbon atoms, or amino; R² is straight or branchedchain alkyl of 1 to 4 carbon atoms, or OR' wherein R' is straight orbranched chain alkyl of 1 to 4 carbon atoms, straight or branched chainalkenyl of 2 to 4 carbon atoms, or alkoxyalkyl of 2 to 4 carbon atoms;R³ is straight or branched chain alkyl of 1 to 6 carbon atoms, or phenylunsubstituted or substituted by alkyl of 1 or 2 carbon atoms, alkoxy of1 or 2 carbon atoms, fluorine, chlorine, bromine, cyano, nitro,trifluoromethyl, or thioalkyl of 1 to 4 carbon atoms; R⁴ is straight orbranched chain alkyl of 1 to 4 carbon atoms; and R⁵ is straight orbranched chain alkyl of 1 to 4 carbon atoms, or benzyl.
 4. A compositionaccording to claim 1 whereinR¹ is alkyl of 1 or 2 carbon atoms, oramino; R² is alkoxy of 1 to 4 carbon atoms; R³ is alkyl of 1 or 2 carbonatoms, or phenyl unsubstituted or substituted by alkyl of 1 or 2 carbonatoms, chlorine, bromine, cyano, nitro, or thioalkyl of 1 or 2 carbonatoms; R⁴ is straight or branched chain alkyl of 1 to 4 carbon atoms;and R⁵ is straight or branched chain alkyl of 1 to 4 carbon atoms, orbenzyl.
 5. A composition according to claim 1 whereinR¹ is methyl, oramino; R² is ethoxy, or propoxy; R³ is methyl, phenyl, nitrophenyl,thiomethylphenyl, or cyanophenyl; R⁴ is ethyl, or isopropyl; and R⁵ ismethyl, ethyl, or benzyl.
 6. A composition according to claim 1 whereinthe compound is ##STR21##
 7. A composition according to claim 1 whereinthe compound is ##STR22##
 8. A composition according to claim 1 whereinthe compound is ##STR23##
 9. A composition according to claim 1 whereinthe compound is ##STR24##
 10. A composition according to claim 1 whereinthe compound is ##STR25##
 11. A composition according to claim 1 whereinthe compound is ##STR26##
 12. A composition according to claim 1 whereinthe compound is ##STR27##
 13. A composition according to claim 1 whereinthe compound is ##STR28##
 14. A composition according to claim 1 whereinthe compound is ##STR29##
 15. A composition according to claim 1 whereinthe compound is ##STR30##
 16. A composition according to claim 1 in oraladministration form.
 17. A composition according to claim 1 inparenteral administration form.
 18. A method of effecting coronaryvessel dilation in humans and other animals and treating hypertension inhumans and other animals which comprises administering to such human oranimal a coronary vessel dilating amount or an antihypertensive amountof a compound of the formula: ##STR31## wherein R¹ is hydrogen, straightor branched chain lower alkyl, or amino;R² is straight or branched chainlower alkyl or OR' wherein R' is straight or branched chain lower alkyl,lower alkenyl, lower alkynyl or alkoxyalkyl of 2 to 4 carbon atoms; R³is straight or branched chain alkyl of 1 to 6 carbon atoms; straight orbranched chain alkenyl of 2 to 6 carbon atoms; straight or branchedchain alkynyl of 2 to 6 carbon atoms; or unsubstituted or substitutedphenyl or naphthyl which when substituted bears 1, 2 or 3 of the same ordifferent substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, azido, cyano,phenyl, nitro, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in thealkoxy moiety and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkylmoiety wherein n is 0, 1 or 2; R⁴ is straight or branched chain alkyl of1 to 6 carbon atoms, straight or branched chain alkenyl of 2 to 6 carbonatoms, or straight or branched chain alkynyl of 2 to 6 carbon atoms; andR⁵ is straight or branched chain alkyl of 1 to 6 carbon atoms, straightor branched chain alkenyl of 2 to 6 carbon atoms, straight or branchedchain alkynyl of 2 to 6 carbon atoms, or benzyl.
 19. A method accordingto claim 18 whereinR¹ is straight or branched chain alkyl of 1 to 4carbon atoms, or amino; R² is straight or branched chain alkyl of 1 to 4carbon atoms, or OR' wherein R' is straight or branched chain alkyl of 1to 4 carbon atoms, straight or branched chain alkenyl of 2 to 4 carbonatoms, straight or branched chain alkynyl of 2 to 4 carbon atoms, oralkoxyalkyl of 2 to 4 carbon atoms; R³ is straight or branched chainalkyl of 1 to 6 carbon atoms; straight or branched chain alkenyl of 2 to6 carbon atoms; straight or branched chain alkynyl of 2 to 6 carbonatoms; phenyl unsubstituted or substituted by 1 or 2 of the same ordifferent substituents selected from the group consisting of alkyl of 1to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen, azido, cyano,nitro, trifluoromethyl, carbalkoxy of 1 to 4 carbon atoms in the alkoxymoiety and SO_(n) -alkyl of 1 to 4 carbon atoms in the alkyl moietywherein n is 0, 1 or 2; or naphthyl; R⁴ is straight or branched chainalkyl of 1 to 4 carbon atoms, straight or branched chain alkenyl of 2 to4 carbon atoms or straight or branched chain alkynyl of 2 to 4 carbonatoms; and R⁵ is straight or branched chain alkyl of 1 to 4 carbonatoms, straight or branched chain alkenyl of 2 to 4 carbon atoms,straight or branched chain alkynyl of 2 to 4 carbon atoms, or benzyl.20. A method according to claim 18 whereinR¹ is straight or branchedchain alkyl of 1 to 4 carbon atoms, or amino; R² is straight or branchedchain alkyl of 1 to 4 carbon atoms, or OR' wherein R' is straight orbranched chain alkyl of 1 to 4 carbon atoms, straight or branched chainalkenyl of 2 to 4 carbon atoms, or alkoxyalkyl of 2 to 4 carbon atoms;R³ is straight or branched chain alkyl of 1 to 6 carbon atoms, or phenylunsubstituted or substituted by alkyl of 1 or 2 carbon atoms, alkoxy of1 or 2 carbon atoms, fluorine, chlorine, bromine, cyano, nitro,trifluoromethyl, or thioalkyl of 1 to 4 carbon atoms; R⁴ is straight orbranched chain alkyl of 1 to 4 carbon atoms; and R⁵ is straight orbranched chain alkyl of 1 to 4 carbon atoms, or benzyl.
 21. A methodaccording to claim 18 whereinR¹ is alkyl of 1 or 2 carbon atoms, oramino; R² is alkoxy of 1 to 4 carbon atoms; R³ is alkyl of 1 or 2 carbonatoms, or phenyl unsubstituted or substituted by alkyl of 1 or 2 carbonatoms, chlorine, bromine, cyano, nitro, or thioalkyl of 1 or 2 carbonatoms; R⁴ is straight or branched chain alkyl of 1 to 4 carbon atoms;and R⁵ is straight or branched chain alkyl of 1 to 4 carbon atoms, orbenzyl.
 22. A method according to claim 18 whereinR¹ is methyl, oramino; R² is ethoxy, or propoxy; R³ is methyl, phenyl, nitrophenyl,thiomethylphenyl, or cyanophenyl; R⁴ is ethyl, or isopropyl; and R⁵ ismethyl, ethyl, or benzyl.
 23. A method according to claim 18 wherein thecompound is ##STR32##
 24. A method according to claim 18 wherein thecompound is ##STR33##
 25. A method according to claim 18 wherein thecompound is ##STR34##
 26. A method according to claim 18 wherein thecompound is ##STR35##
 27. A method according to claim 18 wherein thecompound is ##STR36##
 28. A method according to claim 18 wherein thecompound is ##STR37##
 29. A method according to claim 18 wherein thecompound is ##STR38##
 30. A method according to claim 18 wherein thecompound is ##STR39##
 31. A method according to claim 18 wherein thecompound is ##STR40##
 32. A method according to claim 18 wherein thecompound is ##STR41##
 33. A method according to claim 18 wherein theadministration is oral.
 34. A method according to claim 18 wherein theadministration is parenteral.